Cigarette smoke is the dominant cause of lung cancer in the United States, accounting for an estimated 90% of all cases [1]. However, the damage caused by cigarette smoke is not limited solely to the lung, but rather constitutes a ‘field of injury’ throughout the entire respiratory tract [2-6]. An important product of the field of injury hypothesis is the ability to glean clinically relevant information from cells collected in regions of the respiratory tract, such as the bronchial airway, that can be obtained in a less invasive manner than is typical of collecting primary lung tissue. Based on this approach, a gene expression-based biomarker measured in the cytologically normal bronchial airway epithelium that can distinguish smokers with and without lung cancer has been developed [7]. This airway gene expression biomarker achieved 83% accuracy in predicting whether a smoker had a lung tumor in a prospective test set, and 94% accuracy when combined synergistically with clinical variables [7, 8].
Beyond serving as an early diagnostic tool for lung cancer, gene expression changes in the cytologically normal airway epithelium have the potential to improve our understanding of the signaling events deregulated during early stages of lung cancer. Lung cancer development in humans is a complex process involving multiple aberrant events that, when accumulated, lead to deregulation of crucial cell functions, including cell survival and proliferation. In primary tumors resected from patients with lung cancer, many signaling pathways have previously been found to be deregulated, such as p53, RAS and phosphatidylinositol 3-kinase (PI3K) [9-11]. Additionally, studies in the field of injury and field cancerization have found that some of the molecular changes presumed to be early in tumorigenesis are also reflected in histologically normal cells both neighboring and more distal to the primary tumor. For example, the same p53 mutation or loss of heterozygosity at a specific chromosomal region have been identified throughout the entire respiratory tract [5, 12].
Insight into the deregulation of oncogenic pathways in cytologically normal bronchial airway cells from smokers with lung cancer will help elucidate mechanisms involved in the progression into malignancy. Furthermore, understanding which pathways are deregulated could lead to therapeutic and chemoprophylactic opportunities at the pre-malignant stage of lung cancer.